Though epidemiological studies have demonstrated an inverse association between high-density lipoprotein cholesterol (HDL-C) levels and coronary heart disease (CHD), clinical trials have failed to prove that raising HDL level decreases future cardiovascular events. The roles of HDL in CHD are still poorly understood. Our long term goal is to understand how the anti-atherogenic properties of HDL can be manipulated for preventive and therapeutic purposes. The objective of this revised proposal is to identify the links between HDL particles and vascular remodeling and to reveal the underlying mechanisms responsible for the cardio- protective effects of HDL. HDL is the most complex lipoprotein class comprised of heterogeneous particles differing in size, composition, and -most importantly- key functions which include cholesterol efflux, anti-oxidant, and anti-inflammatory activities. Our preliminary studies indicate that levels of apolipoprotein A-I-containing HDL particles (-1, -2 and pre-1) are significantly better predictors of CHD risk than HDL-C level in both primary and secondary prevention; that an increase in -1 level is significantly associated with decreased progression of coronary artery stenosis, as assessed by angiography; and that cell-cholesterol efflux, via ABCA1, ABCG1, and SRBI is HDL-particle specific. On the basis of these studies, our central hypothesis is that HDL particles have a significant role in plaque morphology and progression, driven by their specific functions, which are dependent on their composition. The central hypothesis will be tested by pursuing three specific aims. In Aim 1, we will evaluate associations between HDL particles and soft (non-calcified) and calcified plaque volumes measured by MD-CTA of the coronary arteries. Data collected from 544 CHD patients before and after a 30-month intervention will be analyzed in both cross-sectional and prospective designs. In Aim 2, we will elucidate the underlying mechanisms by which HDL particles influence plaque progression. We will determine and compare the functionality (cell cholesterol efflux, anti-inflammatory, and anti-oxidative capacity) of total HDL and 5 major HDL subpopulations (pre1, -1, -2, -3, and -4) isolated from a subgroup of CHD patients and from healthy controls. In Aim 3, we will elucidate the effects of the protein and lipid composition of total HDL and the 5 major HDL particles on HDL functions: cell cholesterol efflux, oxidation, and inflammation. The proposed work is innovative because HDL particles will be directly related to coronary plaque morphology (soft, fibrous and calcified plaque volume and geometry) and HDL functionality. The work is significant because it will provide a better understanding of the functionality and the patho-physiological significance of HDL and its particles in cardiovascular and possibly other diseases. The knowledge gained in these studies may lead to therapies that not only raise HDL-C level but also improve HDL functionality for the treatment of CHD, which is still the number one killer in the USA.